Research in this project is directed at understanding the mechanisms of HIV-1 infection, particularly in macrophages, and in developing an effective strategy to prevent and/or inhibit infection. Immunodeficiency, the consequence of HIV-1 infection, predisposes the host to opportunistic infections. In turn, opportunistic infections influence target cell susceptibility to HIV-1 infection and replication.Using M. avium as a model co-pathogen, we have defined multiple viral permissive factors. Moreover, immune activation as occurs in tonsils and non-infectious mucosal inflammatory lesions may also be associated with proximal sites of viral replication. These connections between activation/inflammation and enhancement of HIV-1 infection warrant further elucidation of the factors promoting permissiveness to HIV-1. The tonsil represents an unique microenvironment possessing a large reservoir of activated and highly susceptible HIV targets. By isolating and culturing tonsil cells with HIV, phenotypic, functional and molecular correlates of enhanced susceptibility, as compared to less sensitive peripheral blood mononuclear cells, can be established and provide insight into interventional targets. In an extension of these studies, adherent human peripheral blood monocyte-derived macrophages were exposed to R5 tropic HIV to enable cell surace interactions, and the macrophages monitored for signal transduction, expression of immediate early genes, and genes associated with viral replication. As the association between signaling cascades, gene transcription and macrophage-specific viral dynamics is elucidated, new strategies to interfere with HIV replication and re-infection may emerge.